The field of the invention is a novel peroxidase.
Intracellular amyloid-β peptide (Aβ) and its aggregates are thought to be the neurotoxic agents in Alzheimer's disease (AD) (1-3). Important cytopathologies in AD include loss of iron homeostasis; mitochondrial complex IV dysfunction; oxidative stress (4-7); and cholinergic, dopaminergic, and serotonergic dysfunctions. These cytopathologies play a role in subsequent cognitive impairment (8). Although the molecular link between Aβ and the important cytopathologies seen in AD is not fully understood, our earlier work produced strong evidence that heme may play a key role in the molecular link between Aβ and these cytopathologies. We found that heme metabolism is altered in AD brain (9); that the complex phenotype of heme deficiency (10, 11) is associate with important cytopathologies in AD (10, 11); and that heme readily binds with Aβ, forming an Aβ-heme complex (9). We proposed a model in which excessive Aβ in AD brain binds to regulatory heme, creating a functional heme deficiency (9). Frey and coworkers (12) demonstrated the inactivation of muscarinic acetylcholine receptors by oxidative damage catalyzed by a low-molecular weight substance enriched from AD brain; heme was proposed to be involved in this inactivation. It has been previously demonstrated that heme prevented aggregation of Aβ(1-40) and Aβ(1-42)(13). We have published aspects of the present invention (Atamna H & Boyle, K (2006) Proc Natl Acad Sci USA 103, 3381-3386).